ENDO180 Receptor
ENDO180, also known as CD280, uPARAP (urokinase plasminogen activator receptor associated protein) and mannose receptor C type 2 (MRC2), is a recycling endocytic receptor that directs bound ligands to degradation in the endosomes. It is part of a triple complex with urokinase type plasmin activator (uPA) and urokinase-type plasmin activator receptor (uPAR), thus being involved in the production of plasmin from plasminogen. Plasmin, in turn, is known to play a role in both extracellular matrix (ECM) turnover and proteolytic conversion of latent TGF-beta into its active form.
In addition to its role in the production of plasmin, the triple complex was shown to be involved in the activation of matrix metalloproteinase (MMP) proenzymes, to act on fibrin to bind several collagens and in general turnover of extracellular matrix. This complex also takes part in cell adhesion and signal transduction (Bherendt et al, 2000. JBC 275:1993-2002).
ENDO180 is a recycling endocytic receptor that functions in cell motility and remodeling of the extracellular matrix by promoting cell migration and uptake of collagens for intracellular degradation (Niels. 2004 Biol Chem. 385(2):103-36; Kjoller et al, 2004 Exp Cell Res. 293(1):106-16; Wienke et al., 2007 Cancer Res. 67(21):10230-40). ENDO180 shares homology with the macrophage mannose receptor family: mannose receptor, phosphlipase A2 and DEC-205/MR6 (Isacke et al., 1990 Mol. Cell. Biol. 10:2606-2618; Sheikh et al., 2000, J. Cell. Sci. 113: 1021-1032; Behrendt et al., 2000, J. Biol. Chem. 275: 1993-2002). This family grouping is based on an overall structural conservation: a large extracellular domain comprising an N-terminal signal sequence followed by a cysteine-rich domain, a fibronectin type II domain (FNII), and 8 or 10 C-type lectin-like domains (CTLDs) and small transmembrane and intracellular domains (˜66 amino acids together). As a family, these receptors have two striking features: First, although they belong to the large C-type lectin superfamily, they uniquely contain multiple CTLDs within a single polypeptide backbone (Taylor M. E., 1997 Glycobiology 7: v-vii; McKay et al, 1998, Eur. J. Immunol. 28: 4071-4083; Howard and Isacke, 2002, supra). Second, they share the ability to be recycled between the plasma membrane and intercellular compartments of the cell (Isacke et al, 1990, supra; Zvaritch et al., 1996, J. Biol. Chem. 271: 250-257). ENDO180 is unusual in the family of mannose receptors in that it is targeted from the plasma membrane to the recycling endosomes rather than to a late endosome/lysosome compartment (Howard and Isacke, 2002 supra).
ENDO180 is localized on the cell surface, in clathrin coated pits (Isacke et al., 1990 Mol. Cell. Biol. 10: 2606-2618; Sheikh et al., 2000, J. Cell. Sci. 113: 1021-1032) and in endosomes. It is mainly expressed in fibroblasts, endothelial cells and macrophages. In situ hybridization showed its expression in highly vascularized organs. ENDO180 has also been found in bone-forming regions in mouse embryos (Wu et al., 1996, J. Biol. Chem. 271:21323-21330), and in osteoblasts and osteocytes at sites of endochondral and intramembraneous ossification during development (Engelholm et al., 2001, Trends Cardiovasc. Med. 11:7-13.
The following patent publications also relate to the ENDO180 receptor: U.S. Pat. No. 6,117,977; U.S. Pat. No. 7,399,468; WO 97/40154 and WO 00/58473. PCT Patent Publication No. WO 2004/100759 and US Patent Publication Nos. 2007/0072244 and 2009/0202566 to the assignee of the present invention and hereby incorporated by reference in their entirety relate to methods of identifying compounds capable of modulating human ENDO180 receptor activity.
Antibody Therapy
The search for new therapies to treat cancer and other diseases has resulted in the development of human and humanized antibodies capable of inhibiting receptor function. International patent publication WO 2006/023491 provides a method of RNA interference, which comprises contacting the cell with a fusion protein-double stranded RNA complex, the complex comprising the double stranded RNA segment containing a double stranded RNA of interest and a fusion protein which is an antibody Fab fragment-protamine fusion protein.